Citations

CRISPR/Cas9 technology-mediated genome editing has significantly improved inactivation of genes both in vitro and in vivo in many organisms in a targeted manner. This study reports a novel CRISPR-based vector system for tissue-specific gene inactivation in zebrafish. In this vector, the cardiac-specific, cardiac myosin light chain 2 ( cmlc2) promoter drives the Cas9 expression to silence the neuropilin1(nrp1) gene in cardiomyocytes in a heat-shock inducible manner. This vector system establishes an inimitable tool to regulate the gene knockout in both the developmental and adult stages. Hence, it widens the possibility of loss-of-function studies in zebrafish at different stages of development. In contrast to mammals, adult zebrafish hearts can regenerate after an injury. Neuropilins (nrp) are co-receptors that have been reported earlier to play crucial roles in zebrafish heart regeneration. Using this novel tool, we investigated the role of neuropilin isoforms, nrp1a and nrp1b, in response to cardiac injury and regeneration in adult zebrafish hearts. We observed that both the isoforms ( nrp1a and nrp1b ) are upregulated in the injured heart. Interestingly, the nrp1b -knockout significantly altered heart regeneration and reduced heart function, including heart rate, ejection fraction, and fractional shortening in the adult zebrafish. Moreover, the knockdown of nrp1b , but not nrp1a, further induces the cardiac remodeling genes activation in response to cryoinjury. These results identify a crucial role for nrp1b isoform in zebrafish heart function. To our knowledge, this is the first study where we have reported a heat shock-mediated conditional knockdown of nrp1a and nrp1b isoforms in the heart by using CRISPR/Cas9 technology and reveal a new molecular role of neuropilins in cardiac regeneration.

AbstractObjectiveTo discover a novel peptoid antagonist that targets the interleukin‐15 (IL‐15) receptor and to evaluate its therapeutic efficacy in the treatment of inflammation and arthritis.MethodsA new compound (IFRA3, interleukin‐15 receptor antagonist 3) was discovered using a unique on‐bead two‐colour combinatorial cell screening of a peptoid library. The interaction of IFRA3 with IL‐15 receptor was assessed by in vitro pull‐down and thermal shift assays. The efficacy of IFRA3 in treating inflammation and arthritis was evaluated in mouse models.ResultsIFRA3Q1 (a tetrameric derivative of IFRA3) inhibited the activity of IL‐15 and suppressed CTLL‐2 cell proliferation (which depends on IL‐15 activity). IFRA3Q1 exhibited strong in vivo anti‐inflammatory activity in carrageenan‐induced inflammation in mice. Furthermore, IFRA3Q1 inhibited collagen‐induced arthritis in DBA/1J mice.ConclusionBy binding to and inhibiting the function of IL‐15 receptor, IFRA3Q1 exhibited significant anti‐arthritis activity. Our findings suggest that IFRA3Q1 represents a new paradigm for arthritis therapy by targeting IL‐15 signalling.

Abstract Purpose To determine if the COVID‐19 pandemic has further exacerbated racial disparities in late‐stage presentation of breast, colorectal, lung, and prostate cancers. Methods We conducted a registry‐based retrospective study of patients with newly reported diagnoses of breast, colorectal, lung, and prostate cancers between March 2019–June 2019 (pre‐COVID‐19) and March 2020–June 2020 (early‐COVID‐19). We compared the volume of new diagnoses and stage at presentation according to race between both periods. Results During the study period, a total of 3528 patients had newly diagnosed cancer; 3304 of which had known disease stages and were included in the formal analyses. 467 (14.1%) were Blacks, and 2743 were (83%) Whites. 1216 (36.8%) had breast, 415 (12.6%) had colorectal, 827 (25%) had lung, and 846 (25.6%) had prostate cancers, respectively. The pre‐COVID‐19 period included 2120 (64.2%), and the early‐COVID‐19 period included 1184 (35.8%), representing a proportional 44.2% decline in the volume of new cases of breast, colorectal, lung, and prostate cancers, p < 0.0001. Pre‐COVID‐19, 16.8% were diagnosed with metastatic disease, versus 20.4% early‐COVID‐19, representing a proportional increase of 21.4% in the numbers of new cases with metastatic disease, p = 0.01. There was a non‐significant proportional decline of 1.9% in Black patients diagnosed with non‐metastatic breast, colorectal, lung, and prostate cancers early‐COVID‐19 ( p = 0.71) and a non‐significant proportional increase of 7% in Black patients diagnosed with metastatic disease ( p = 0.71). Difference‐in‐difference analyses showed no statistically significant differences in metastatic presentation comparing Black to White patients. Conclusion While we identified substantial reductions in the volume of new cancer diagnoses and increases in metastatic presentations due to the COVID‐19 pandemic, the impact was similar for White and Black patients.